Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness.
Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness.
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DOI：
10.1161/hypertensionaha.113.01967
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Jaisser F
中科院分区：
文献类型：
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作者：
Galmiche G;Pizard A;Gueret A;El Moghrabi S;Ouvrard-Pascaud A;Berger S;Challande P;Jaffe IZ;Labat C;Lacolley P;Jaisser F
动脉僵硬被认为是许多心血管疾病的危险因素。通过与盐皮质激素受体(MRS)的结合和激活，醛固酮是控制肾脏钠重吸收的主要血压调节器。虽然临床和实验数据都表明，醛固酮激活MR参与了动脉硬化，但其分子机制尚不清楚。除了肾脏，MR在血管内皮细胞和血管平滑肌细胞(VSMCs)中都有表达，但VSMC MR在醛固酮诱导的血管僵硬中的具体作用仍有待探讨。为了解决这个问题，我们建立了一种VSMC中MR有条件失活的小鼠模型(MRSMKO)。MRSMKO小鼠在肾脏钠处理或血管结构方面没有变化，但与对照仔鼠相比，它们的血压降低了。在体内，与对照组相比，突变小鼠的大血管呈现出正常的弹性特性，而颈动脉则显示出较小的直径。正如预期的那样，在醛固酮/盐攻击后，对照组小鼠的动脉硬度增加；然而，MRSMKO小鼠的动脉硬度保持不变，血管胶原/弹性蛋白比率没有明显变化。相反，我们发现在MRSMKO小鼠中，纤维连接蛋白/α5亚单位整合素的比率发生了深刻的变化，因为在缺乏血管平滑肌细胞的小鼠中，醛固酮/盐刺激诱导α5的表达被阻止。总之，我们的数据显示，在醛固酮/盐高血压模型中，血管平滑肌细胞中特异的MR激活导致动脉硬化，其通过调节细胞-基质附着蛋白而不依赖于主要的血管结构变化。
Arterial stiffness is recognized as a risk factor for many cardiovascular diseases. Aldosterone via its binding to and activation of the mineralocorticoid receptors (MRs) is a main regulator of blood pressure by controlling renal sodium reabsorption. Although both clinical and experimental data indicate that MR activation by aldosterone is involved in arterial stiffening, the molecular mechanism is not known. In addition to the kidney, MR is expressed in both endothelial and vascular smooth muscle cells (VSMCs), but the specific contribution of the VSMC MR to aldosterone-induced vascular stiffness remains to be explored. To address this question, we generated a mouse model with conditional inactivation of the MR in VSMC (MRSMKO). MRSMKO mice show no alteration in renal sodium handling or vascular structure, but they have decreased blood pressure when compared with control littermate mice. In vivo at baseline, large vessels of mutant mice presented with normal elastic properties, whereas carotids displayed a smaller diameter when compared with those of the control group. As expected after aldosterone/salt challenge, the arterial stiffness increased in control mice; however, it remained unchanged in MRSMKO mice, without significant modification in vascular collagen/elastin ratio. Instead, we found that the fibronectin/α5-subunit integrin ratio is profoundly altered in MRSMKO mice because the induction of α5 expression by aldosterone/salt challenge is prevented in mice lacking VSMC MR. Altogether, our data reveal in the aldosterone/salt hypertension model that MR activation specifically in VSMC leads to the arterial stiffening by modulation of cell-matrix attachment proteins independent of major vascular structural changes.